Abstract: Helicobacter pylori chronically infects 50% of the world?s population and is a significant cause of gastric cancer. In the stomach, the bacterium interacts with host cells and elaborates virulence factors that directly influence disease etiology. Our understanding of the molecular basis for H. pylori pathogenesis was advanced by the discovery of a pathogenicity island (PAI) that encodes a Type IV secretion system (T4SS) as well as the potent cytotoxin-associated gene A (CagA). These factor, along with another cytotoxin, VacA, all elaborate host cell changes that likely contribute to gastric disease progression. The use of small animal models is paramount to elucidating bacterial and host factors that contribute to H. pylori-induced gastric cancer. Of the available small animal models, the Mongolian gerbil best simulates parameters found in humans and these animals reproducibly develop gastric cancer in a period of 8-12 weeks after infection with H. pylori strain 7.13. The 7.13 gastric cancer model has now been minimally used to investigate the contribution of virulence factors and particular host signaling pathways to cancer development. However, this model has not been widely utilized in the H. pylori field due to several reasons, including loss of virulence upon in vitro passage. Overall, reliance of the H. pylori field on a single strain to study the molecular events leading to gastric cancer is less than ideal. Thus, we have identified and seek to characterize an additional H. pylori strain (USU101) that causes gastric cancer in the Mongolian gerbil model. We will directly compare infection, disease etiology and host cell signaling alterations induced by USU101 and 7.13. Furthermore, we will construct isogenic mutant strains missing the key virulence factors, cagA, vacA, and cagE, along with the corresponding complementation strains, and assess their contribution to gastric cancer development and host signaling. En masse, we predict that the description and detailed characterization of USU101 as an alternative means to induce and study gastric cancer will provide a valuable resource to the community. !